Inhibition of phosphatidylinositol 3-kinase with 17 β-hydroxywortmannin and analogs thereof

Abstract

17 beta -hydroxywortmannin and certain of its analogs are inhibitors of phosphatidylinositol 3-kinase. The compounds are particularly useful for inhibiting phosphatidylinositol 3-kinase in mammals and for treating phosphatidylinositol 3-kinase-dependent conditions, especially neoplasms, in mammals.

We claim: 
     
       1. A method of inhibiting phosphatidylinositol 3-kinase in a lysed or whole cell comprising contacting said lysed or whole cell with a compound of formula I ##STR4## wherein R is H or acetoxy; R 1  is C 1  -C 6  alkyl;   R 2  is hydrogen, C 1  -C 6  alkyl, or a group of the formula --COOR 3  ; and   R 3  is H or C 1  -C 6  alkyl.   
     
     
       2. The method of claim 1 wherein R 1  is methyl and R 2  is H. 
     
     
       3. The method of claim 2 wherein R is H. 
     
     
       4. The method of claim 2 wherein R is acetoxy. 
     
     
       5. The method of claim 1 wherein said method is carried out in vitro. 
     
     
       6. The method of claim 1, wherein said method is carried out in vivo. 
     
     
       7. A method for inhibiting phosphatidylinositol 3-kinase in a mammal comprising administering to said mammal a phosphatidylinositol 3-kinase inhibiting amount of formula I ##STR5## wherein R is H or acetoxy; R 1  is C 1  -C 6  alkyl;   R 2  is hydrogen C 1  -C 6  alkyl, or a group of the formula --COOR 3  ; and   R 3  is H or C 1  -C 6  alkyl.   
     
     
       8. The method of claim 7 wherein said mammal is a human. 
     
     
       9. The method of claim 8 wherein R 1  is methyl and R 2  is H. 
     
     
       10. The method of claim 9 wherein R is H. 
     
     
       11. The method of claim 9 wherein R is acetoxy. 
     
     
       12. A method for treating a phosphatidylinositol 3-kinase-dependent condition in a mammal in need of such treatment comprising administering to said mammal a phosphatidylinositol 3-kinase inhibiting amount of a compound of formula I ##STR6## wherein R is H or acetoxy; R 1  is C 1  -C 6  alkyl;   R 2  is hydrogen C 1  -C 6  alkyl, or a group of the formula --COOR 3  ; and   R 3  is H or C 1  -C 6  alkyl.   
     
     
       13. The method of claim 12 wherein said phosphatidylinositol 3-kinase-dependent condition is a neoplasm. 
     
     
       14. The method of claim 13 wherein said mammal is a human. 
     
     
       15. The method claim 14 wherein R 1  is methyl and R 2  is H. 
     
     
       16. The method of claim 15 wherein R is H. 
     
     
       17. The method of claim 15 wherein R is acetoxy. 
     
     
       18. The method of claim 14 wherein R 1  is methyl, R 2  is a group of the formula --COOR 3 , and R 3  is H. 
     
     
       19. The method of claim 18 wherein R is H. 
     
     
       20. The method of claim 18 wherein R is acetoxy.